b i o g e n i d e c M S P h y S i c i a n S u M M i t :

1st choices & changes in Mssaturday, 8th June 2013

chairs: Xavier Montalban, spain & hans-peter hartung, germany

09:00 The Early Face of MS Mar Tintoré, Spain

09:30 Changes in the CNS Hans Lassmann, Austria

10:00 Targets & Therapies Ralf Gold, Germany

10:30 Break

11:00 The Efficacy Picture of Oral DMF Xavier Montalban, Spain

11:30 Managing a New Therapy Eva Havrdová, Czech Republic

12:00 Lunch

13:00 Goals & Individuals Gavin Giovannoni, United Kingdom

13:30 When Goals are Not Met Hans-Peter Hartung, Germany

14:00 Weighing Risks Ludwig Kappos, Switzerland

14:30 Break

15:00 Efficacy Matters with Natalizumab Carlo Pozzilli, Italy

15:30 Neurons Firing – A Roundtable Discussion Moderator: Hans-Peter Hartung, Germany

16:00 End of Summit

b i o g e n i d e c M S P h y S i c i a n S u M M i t :

1st choices & changes in Mssaturday, 8th June 2013

chairs: Xavier Montalban, spain & hans-peter hartung, germany

Slide 1: Introduction

Good afternoon. My task is to communicate to you a shift in the paradigm in relation to the treatment of MS and how this relates to setting goals of treatment for individual patients.

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Slide 2: Balance

Although treatment involves both risks and benefits there is no risk:benefitratio that fits everyone and at the end of the day it largely boils down to an informed individual decision.

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Slide 3: How serious a disease is MS

Before making a decision about risk I would like to review the risks of untreated or inadequately treated MS.

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Slide 4: Lifespan

Mortality; MS is a serious disease and reduces life expectancy by approximately 10 years. This Norwegian data set is an example of the impact of MS on survival.

Slide 5: 21-year survival data

Can we impact on mortality? This is the 21-year follow-up data of the pivotal IFNbeta-1b data demonstrating that simply starting IFN-beta 3 years early reduces MS-related mortality at 21 years by close to 50%. I can't think of any better data to support early treatment than this. The real question is: 'If IFNbeta, a moderately effective therapy, can have this sort of impact what will be the impact of more effective DMTs?'

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Slide 6: QoL

The impact that MS has on QoL is beyond doubt. You just need to come to my follow-up MS clinic to see this. In this study we did to convince NICE of the benefits of natalizumab. NICE is the organisation that assesses the cost-effectiveness of drugs for the NHS. It is very sobering; people living in the UK rated the QoL of Msers with and EDSS of 8 or 9 as having a QoL being worse than death. Health Economists tell me that no other disease has previously scored negatively using this study design. The implications of this is that if we as a society adopted euthanasia we would want to target Msers with advanced disease.

Slide 7: Employment

Employment; is probably the most sensitive integrator of health. In Denmark the median time to becoming unemployed is 10 years. In the UK this figure is 8.5 years and occurs at an early stage of the disease. The mean EDSS at which 50% of Msers are unemployed is 3.5; a level that is not associated with much physical disability.

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Slide 8: Divorce

Msers are also more likely to get divorced or separate from their partners. This is not due to physical disability when we compare Msers to disease controls, namely patients with RA, the divorce rate of Msers is remains higher than expected.

What is driving early unemployment and the breakdown of relationships?

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Slide 9: CIS and cognition

I suspect it is linked to the impact that MS has on cognition and mood. This study demonstrates that significant cognitive impairment is present from the earliest stages of the disease. In this study of CISers over 50% had evidence of cognitive impairment in at least 2 cognitive domains. In modern knowledge-based economies it is easy to see why this may lead to early unemployment.

Slide 10: Benign MS

One argument against the early aggressive treatment paradigm is that if you treat everyone you are going to be treating a large number of Mserswith benign disease who don't need a drug. I am not sure what benign disease is. In this study on benign MS, by Maria Pia Amato in Florence, shows that Msers' with 'benign disease' as defined by EDSS have a large burden of hidden MS symptoms with 50% of having cognitive impairment, depression or fatigue. The problem with our field is that we tend see MS through EDSS spectacles. We need to acknowledge that MS have impacts on QoL and neurological functioning outside of the pyramidal system.

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Slide 11: Clinical prognostic factors

Although we have identified many factors that favours a good prognosis in MS at a group level it is very difficult to use them on an individual level. I have seen too many examples of Mser being labelled as having benign MS early in the course of the disease only to present several years later with severe or progressive disease. I personally would like to ban the use of term benign MS early in the disease course. Benign MS is a term that can only be used after 15 to 20 years of having the disease.

Slide 12: Relapses

How often have you heard that relapses are irrelevant to the disease course? I disagree. Firstly, if you have MS having relapses is a reminder that you have MS. Secondly, relapses are in themselves drivers of disability. In this study from Fred Lublin 30-40% of Msers who have had a relapse, have persistent disability 3 months after the relapse. Poor recovery from relapses are clearly one of the drivers of disability progression and is an argument to try eliminate relapses.

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Slide 13: Theoretical Model

This and other data presented at this meeting supports the treatment strategy of early aggressive treatment to prevent or reduce disability.

Slide 14: What is your treatment philosophy?

Given the information Mar Tintore and I have presented today, what is your treatment philosophy? At present we tend to use moderately effective platform injectable therapies that reduce the frequency and severity of relapses, but have a relatively small effect on long-term disability.

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Slide 15: Early aggressive therapy

The new paradigm is to adopt an early more aggressive therapy approach using more effective therapies early in the course of the disease before Msers have acquired irreversible disease. The so called "hit hard an early paradigm". One criticism of this approach is the hypothesis that MS is not an inflammatory disease, but a neurodegenerative disease with inflammation simply being a secondary response and that suppressing inflammation will not prevent the development of SPMS. This may be the case and we will only get the answer to this question in 15-20 years.

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Slide 16: 15-20 year experiment

This experiment is currently running and we will see if Msers rendered disease activity free early in the course of the disease will come back with SPMS. The question you need to ask yourself is; "Are you prepared to deny your patients more effective treatments whilst we wait for this data to emerge?"

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Slide 17: Risk:Benefits

How do we personalise the risks of treatment and MS on one hand with the potential benefits of MS treatments on the other hand.

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Slide 18: Factors behind risk benefit decisions

There are many factors that underpin individual decisions about when to start treatment and what treatment to choose for an individual Mser. What I can say is the field is evolving away from physician-based decision making to make Msers the centre of decision making. For those of us working in Europe the biggest hurdle for us adopting this new paradigm are our regulators and payers who are want us to reduce MS decision making to a simple algorithm. The problem with this approach is that it may have a negative impact on MS outcomes.

Slide 19: MS Decisions are complex

What are regulators or payers are ignoring is how complex decision making is and how many factors we need to take into account when treating MS. They also don't realise that the day-to-day practice of medicine and neurology is a art and necessarily a science.

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Slide 20: Algorithm 1

What is clear is that once you decide to start a treatment you need to monitor Msers to see if the respond to a particular therapy.

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Slide 21: Algorithm 2

Non-responder and those intolerant of therapy need to moved to another treatment or have their therapy escalated.

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Slide 22: Responders vs. Non-responders

At present we monitor response and non-response by monitoring Mserson DMTs using a composite of clinical, MRI and biomarkers (Nabs).

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Slide 23: 100 Msers

Unfortunately, we don't have a way of identifying responders up front. We simply have to take, say 100, Msers and give them a trial of treatment to see who responds or does not respond.

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Slide 24: Responders

In my personal experience only about 20% of MSers can be classified as being responders about 4 years after starting treatment, i.e. those that are free of disease activity. Of the remaining Msers ~40% can be classified as non-responders and 40% as sub-optimal responders with reduced disease activity on treatment, but not having their disease-activity completely suppressed. What is emerging is that clinical and sub-clinical activity predicts a poor long-term outcome. Which under pins the zero tolerance strategy in relation to MS disease activity.

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Slide 25: NEDA

This Zero tolerance strategy that I am proposing is underpinned by principles we have is adopted from rheumatology and oncology. The so called to treat-to-target of no evidence of disease activity, which at present is a composite of being free of relapses, disease progression, new and enlarging T2 lesions and Gd-enhancing lesions. I prefer the term NEDA, or no evidence of disease activity from oncology, as it acknowledges that we are not measuring all disease activity with our current definition.

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Slide 26: Treat-2-Target

NEDA as a concept will allow us to include new technologies in the future. I envisage us including grey matter lesions, normalisation of brain atrophy rates and CSF biomarkers into this definition in the future. So the target may be a moving one as we target other aspects of MS pathology, in particular the degenerative aspects of the disease.

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Slide 27: NEDA Algorithm

To encourage adoption of this concept I have proposed an algorithm for discussion by the MS Community. At present this is being done on our blog, but will be followed shortly by a microsite. Rick Rudick from the Cleveland Clinic is leading the lobby in the US and has held one meeting dedicated to this topic last year and is due to host a second meeting later this yea r in Las Vegas.

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Slide 28: Early treatment

It was clear that when using more effective therapies that the best results are obtained when using the drugs early and not only in MSers with highly active disease.

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Slide 29: Doughnut

The implications of this for Msers cannot be under-estimated. In the UK we are only allowed to escalate therapy if Msers fail platform therapy by having highly active disease, that is two disabling attacks in the last 12 months with MRI evidence of disease progression. This creates a doughnut with a large number of Msers left in no man's land with smouldering MS that all the evidence suggesting that it is priming them for progressive disease. Another concern I have is that as more so called first-line therapies emerge we will be required to cycle them through multiple moderately effective therapies before escalation. Time spent on this bottom tier may prove devastating in the long-term.

Other markers, I am particularly interested in including in our definition of NEDA is CSF neurofilaments and brain atrophy. Neurofilaments are axonal proteins that are released in response to damage and predict disease progression. In this study from Jan Lycke's group in Gothenberg you can see the impact of natalizumab on CSF neurofilament levels in RRMS; it normalises it. Unfortunately, it does not quite normalise the levels in SPMSers indicating that in addition to anti-inflammatory measures we need treatments to target delayed neurodegeneration. Similarly, we need drugs to normalise brain atrophy rates.

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Slide 30: Conclusions

In conclusion we have entered the era of personalised medicine. It is time to shift the paradigm and to adopt the concepts of treat-2-target and zero tolerance. We as a group need to ask who is best positioned make risk:benefit decisions around early aggressive therapy. We need to lobby regulators and payers to allow Msers access to these treatments and that using these drugs second or third line may be too late. You also need to ask yourself what is your treatment philosophy? Is it fair to make Mserswait 20 years for the results of the early aggressive treatment paradigm. I would like to remind you that "Time is Brain".

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